Heavy alcohol consumption is associated with hippocampal dysfunction. Evidence suggests that hippocampal-dependent cognitive impairments in alcoholics are a contributing factor in high relapse rates and poor treatment outcomes. Chronic alcohol exposure remodels glutamatergic synapses, and these structural and functional neuroadaptations have been implicated in learning and memory deficits. However, there is a substantial gap in our knowledge about the neural mechanisms that underlie alcohol-associated cognitive decline. In CA1 pyramidal neurons of the hippocampus, voltage-dependent potassium (Kv) channels comprised of Kv4.2 a subunits are enriched in distal dendrites and underlie the subthreshold transient A-type K+ current (ISA). Kv4.2 channels function to critically regulate neuronal signaling by modulating synaptic integration and plasticit. Previous work has shown that surface expression of Kv4.2 is promoted through interaction with a group of proteins called K+ channel interacting proteins (KChIPs). Emerging evidence suggests that there is a functional coupling between Kv4.2 channels and NMDA receptors that may be critical for plasticity and is regulated by KChIP3. Our preliminary data demonstrate that chronic ethanol treatment of organotypic hippocampal slice cultures reduces Kv4.2 channel function and surface expression and enhances Ca2+ transients evoked by back-propagating action potentials (bAPs) in distal apical dendrites of CA1 pyramidal neurons. In addition, chronic ethanol significantly reduced KChIP3 expression and increased NMDA receptor expression. In adult rats, chronic intermittent ethanol (CIE) exposure down-regulates Kv4.2 channel expression and impairs performance on hippocampal-dependent tasks. Thus, our preliminary data have identified Kv4.2 channels and KChIP3 as promising molecular targets that underlie aberrant signal processing in CA1 pyramidal neurons in following chronic alcohol exposure. We have designed a comprehensive yet focused set of studies to test the overarching hypothesis of this proposal that the reduction in Kv4.2 channel function and up-regulation of NMDA receptors by chronic ethanol exposure contributes to enhanced bAP signaling, aberrant plasticity and hippocampal dysfunction. The proposed studies involve a multifaceted approach that involves biochemistry, slice electrophysiology, multielectrode recording, optogenetics, and viral vector technologies to test the following hypotheses: Aim 1) Test the hypothesis that CIE bidirectionally alters expression of Kv4.2 channels and NMDA receptors in the hippocampus through modulation of KChIP3; Aim 2) Test the hypothesis that CIE reduces expression and function of Kv4.2 channels and alters spike timing- dependent synaptic plasticity in the acute slice preparation; and Aim 3) Determine whether CIE alters the cognitive function of the hippocampus and induces aberrant hippocampal plasticity in vivo. These studies will advance our knowledge of the neural mechanisms contributing to ethanol-associated impairments in synaptic plasticity and cognitive function and identify novel therapeutic targets for more effective treatment of alcoholism and alcohol-related problems.